Function and Molecular Mechanism of Acetylation in Autophagy Regulation
Function and Molecular Mechanism of Acetylation in Autophagy Regulation
复制标题
乙酰化在自噬调控中的作用及分子机制
DOI：
10.1126/science.1216990
复制
发表时间：
2012-04-27
期刊：
影响因子：
56.9
通讯作者：
Yu, Li
中科院分区：
文献类型：
--
作者：
Yi, Cong;Ma, Meisheng;Yu, Li
乙酰化和自噬自噬允许细胞在必要时消化自己的成分以在压力条件下生存。Lin等（第477页）和Yi等（第474页）分别描述了哺乳动物细胞和酵母中的信号传导机制，通过该机制，自噬被蛋白质乙酰化调节。在缺乏血清的哺乳动物细胞中，乙酰转移酶TIP 60通过蛋白激酶GSK 3（糖原合成酶激酶3）的磷酸化而被激活。TIP 60的靶点似乎是一种对自噬调节至关重要的蛋白激酶ULK 1。这种激活途径是在没有血清的情况下自噬所必需的，但在缺乏葡萄糖的细胞中自噬不需要。在缺乏氮的酿酒酵母中，发现了另一种乙酰化机制。饥饿导致组蛋白乙酰转移酶Esa 1的激活，它使自噬机制的关键组分Atg 3乙酰化，从而增加了它与另一种自噬蛋白Atg 8的相互作用。乙酰转移酶TIP 60的功能是特异性地促进缺乏生长因子的细胞中的自噬。蛋白质乙酰化是许多细胞过程的关键调控机制。我们使用酿酒酵母的遗传分析，以确定Esa 1作为自噬所需的组蛋白乙酰转移酶。我们进一步鉴定了自噬信号传导组分Atg 3作为Esa 1的底物。具体而言，Atg 3的K19和K48的乙酰化通过控制Atg 3和Atg 8的相互作用和Atg 8的脂化来调节自噬。饥饿诱导短暂的K19-K48乙酰化，通过空间和时间调节的本地化的乙酰化酶Esa 1和脱乙酰化酶Rpd 3的前自噬体结构（PAS）和它们的相互作用与Atg 3。K19-K48乙酰化的减弱与自噬的减弱相关。在去乙酰化酶Rpd 3缺失后增加的K19-K48乙酰化引起增加的自噬。因此，蛋白质乙酰化有助于控制自噬。
Acetylation and Autophagy Autophagy allows cells to digest their own components when necessary to survive stressful conditions. Lin et al. (p. 477) and Yi et al. (p. 474) describe signaling mechanisms in mammalian cells and yeast, respectively, by which autophagy is regulated by protein acetylation. In mammalian cells deprived of serum, the acetyltransferase TIP60 was activated by phosphorylation by the protein kinase GSK3 (glycogen synthase kinase 3). TIP60's target appeared to be a protein kinase central to autophagy regulation, ULK1. This activating pathway was required for autophagy in the absence of serum, but was not needed for autophagy in cells deprived of glucose. In the yeast Saccharomyces cerevisiae starved of nitrogen, another acetylation mechanism was uncovered. Starvation led to activation of the histone acetyltransferase Esa1, which acetylated the protein Atg3, a key component of the autophagy machinery, thus increasing its interaction with another autophagy protein, Atg8. The acetyltransferase TIP60 functions specifically to promote autophagy in cells deprived of growth factors. Protein acetylation emerged as a key regulatory mechanism for many cellular processes. We used genetic analysis of Saccharomyces cerevisiae to identify Esa1 as a histone acetyltransferase required for autophagy. We further identified the autophagy signaling component Atg3 as a substrate for Esa1. Specifically, acetylation of K19 and K48 of Atg3 regulated autophagy by controlling Atg3 and Atg8 interaction and lipidation of Atg8. Starvation induced transient K19-K48 acetylation through spatial and temporal regulation of the localization of acetylase Esa1 and the deacetylase Rpd3 on pre-autophagosomal structures (PASs) and their interaction with Atg3. Attenuation of K19-K48 acetylation was associated with attenuation of autophagy. Increased K19-K48 acetylation after deletion of the deacetylase Rpd3 caused increased autophagy. Thus, protein acetylation contributes to control of autophagy.